Search for: rheumatoid arthritis methotrexate autoimmune disease biomarker gene expression GWAS HLA genes non-HLA genes
| ID | PMID | Title | PublicationDate | abstract |
|---|---|---|---|---|
| 3548731 | Mast cell numbers in rheumatoid synovial tissues. Correlations with quantitative measures | 1987 Feb | Synovial biopsy specimens from 20 patients with rheumatoid arthritis were subjected to quantitative analysis for several parameters of inflammation and for enumeration of synovial tissue mast cells. Strong positive correlations were found between numbers of mast cells per cubic millimeter of synovial tissue and the following synovial tissue parameters: inflammatory index (a quantification of lymphocytic infiltration), Leu-3a grade (T helper/inducer lymphocytes), Leu-1 grade (T lymphocyte), and plasma cell grade. A strong negative correlation was found between the synovial mast cell count and the extent of sublining layer fibrin deposition. Correlations between synovial mast cell count and Leu-2a grade, ratio of Leu-3a grade:Leu-2a grade, OKM1 grade, HLA-DR grade, and lining layer thickness grade did not reach statistical significance. In addition, we obtained synovial specimens from 6 of the patients both before and after long-term therapy with oral methotrexate and from 3 of the patients before, and 1 week after, an intraarticular injection of steroid. The 3 patients who had an intraarticular steroid injection showed a 67-96% decrease in the number of synovial tissue mast cells; there was no significant change in the number of synovial mast cells in the tissues of the 6 patients who received oral methotrexate. These observations are the first documentation of a quantitative relationship between the number of mast cells and the number and phenotypic profile of infiltrating lymphocytes in an inflamed tissue, which in this case, is human synovium. Our findings suggest that mast cells are involved in the pathologic interactions in rheumatoid arthritis and might play a role in the early phases of exacerbations of disease activity. | |
| 2029111 | Influence of methotrexate and azathioprine on radiologic progression in rheumatoid arthrit | 1991 Jun 15 | OBJECTIVE: To compare the effects of azathioprine and methotrexate on progression of radiologic damage in patients with rheumatoid arthritis. DESIGN: Double-blind, randomized 48-week trial. PATIENTS: Sixty-four patients with active rheumatoid arthritis who either have not responded to or who have reacted with side effects to at least parenteral gold and D-penicillamine. INTERVENTIONS: Either azathioprine, 100 mg daily, or methotrexate, 7.5 mg weekly, was administered orally. Depending on the clinical effect after 8 weeks, the dosage was increased to either azathioprine, 150 mg, or methotrexate, 15 mg. The dosages for nonsteroidal anti-inflammatory drugs and prednisone were held stable. MEASUREMENTS: Clinical and laboratory assessments were done by the same physician every 4 weeks for the first 24 weeks and every 8 weeks thereafter. Radiographs of hands, wrists, and feet obtained at baseline and after 24 and 48 weeks were scored by one rheumatologist blinded to medication and clinical findings. MAIN RESULTS: Initial radiologic scores were comparable in both groups and correlated with disease duration (r = 0.38). An intention-to-treat analysis after 24 and 48 weeks showed significantly fewer new erosions in the methotrexate group compared with the azathioprine group (difference, 2.0 [95% CI, 0.2 to 3.9] and 3.5 [CI, 1.3 to 5.8], respectively). The change in total joint score was also significantly less pronounced in the methotrexate group compared with the azathioprine group after 24 weeks (difference, 2.8 [CI, 0.2 to 5.2]) and after 48 weeks (difference, 3.9 [CI, 0.3 to 7.4]). Radiologic stabilization after 48 weeks was present in 10% of the azathioprine group compared with 29% of the methotrexate group. CONCLUSIONS: Patients with rheumatoid arthritis treated with low-dose methotrexate showed significantly less radiologic progression than patients treated with azathioprine. This result suggests that methotrexate therapy is clinically superior in these patients. | |
| 2328562 | Coadministration of naproxen and low-dose methotrexate in patients with rheumatoid arthrit | 1990 Apr | Fifteen patients (30 to 78 years of age) with diagnoses of rheumatoid arthritis were administered oral and intravenous methotrexate (15 mg), alone or with concomitant naproxen (1000 mg/day). Serial blood samples and urine were collected for 24 hours after the dose of methotrexate and were assayed for methotrexate by a specific radioenzymatic method. In twelve patients who completed the study, methotrexate systemic clearance was not statistically different with naproxen (103.3 +/- 35.0 ml/min) versus without naproxen (113.4 +/- 48.3 ml/min; p = 0.37). Oral clearance of methotrexate was not statistically different with naproxen (161.7 +/- 55.0 ml/min) versus without naproxen (176.7 +/- 68.3 ml/min; p = 0.14). Likewise, there was not a significant difference in methotrexate renal clearance or plasma protein binding with or without naproxen. No toxicity was observed when patients received methotrexate alone or with naproxen. This study indicates that concomitant naproxen does not abruptly alter the disposition of low-dose methotrexate in patients with rheumatoid arthritis who have normal renal function. | |
| 2273519 | Azathioprine and methotrexate as combination chemotherapy in rheumatoid arthritis. | 1990 Nov | Azathioprine or methotrexate (MTX) are each established, and comparably effective, therapies for rheumatoid arthritis (RA). An ongoing, still double blind, 3-arm, 24-week study comparing azathioprine or MTX, or azathioprine and MTX in RA is described. With 146 (of 210 total) patients enrolled, it is apparent that all 3 treatment groups demonstrate clinically significant improvement at Week 24. One treatment arm (Group 1) showed a greater degree of improvement in raw mean scores for most outcome variables. Another treatment arm (Group 2) had an adverse effect dropout rate exceeding the sum of adverse effect dropouts from Group 1 and Group 2. Most adverse effects were due to gastrointestinal intolerance. | |
| 1980314 | Combination therapy of rheumatoid arthritis--rationale and overview. | 1990 Nov | Currently available therapeutic agents for the treatment of rheumatoid arthritis are unsatisfactory for many patients, due either to inefficacy, loss of effectiveness with time, or toxicity. One approach is to study drugs in combination, at lower than usual dosages of each, in order to achieve greater efficacy with fewer adverse reactions. To aid in this review of published trials, the various combinations have been arbitrarily divided into combinations of cytotoxic (antiproliferative) drugs with each other, and combinations of noncytotoxic drugs. Of the noncytotoxic combinations, intramuscular gold with D-penicillamine appeared to offer the best results without increased side effects when compared to each one used alone. The most promising cytotoxic combination was methotrexate with azathioprine. | |
| 3946976 | Rheumatoid arthritis associated with expanded populations of granular lymphocytes. | 1986 Mar | Two patients with classic rheumatoid arthritis developed severe neutropenia and increased numbers of large granular lymphocytes in the blood and bone marrow. These lymphocytes exhibited homogeneous surface membrane immunophenotypes of Leu5+, Leu11-, Leu4+, Leu3-, Leu2-, Leu7+ and Leu5+, Leu11+, Leu4+, Leu3-, Leu2+, Leu7-, respectively. In both patients, neutropenia was initially corrected with corticosteroid therapy; long-term improvement followed low-dose oral cyclophosphamide and methotrexate therapies. In these 2 patients and 12 previous patients with rheumatoid arthritis associated with expanded populations of immunophenotypically homogeneous large granular lymphocytes, neutropenia occurred in all 14, thrombocytopenia in 6, anemia in 7, and mild or moderate splenomegaly in 12. In contrast to Felty's syndrome, granular lymphocyte expansions in rheumatoid arthritis usually occur in older patients, may appear simultaneously with arthritis, and are usually associated with normal or elevated blood leukocyte counts. Mild hemocytopenias in these patients can often be managed with observation. Therapy with corticosteroids or immunosuppressive-cytotoxic drugs may be beneficial in more severe cases, but splenectomy is not recommended. | |
| 2180405 | Low-dose methotrexate compared with auranofin in adult rheumatoid arthritis. A thirty-six- | 1990 Mar | Weekly treatment with low-dose oral methotrexate (MTX) was compared with daily auranofin (AUR) treatment in a 36-week double-blind, randomized, multicenter study of 281 patients with active, adult-onset rheumatoid arthritis. Both treatment groups showed significant improvement by the usual measures of clinical efficacy. The response with MTX occurred earlier and was consistently greater than that with AUR. An intent-to-treat analysis showed significantly greater improvement (P less than 0.01) with MTX for painful and swollen joint counts and physician and patient global assessments of disease activity. Adverse reactions were reported more frequently in the AUR group, and more AUR-treated patients were withdrawn from the study because of toxicity. MTX was thus more effective and better tolerated than AUR in this study. | |
| 2390121 | Suppression of rheumatoid factor production by methotrexate in patients with rheumatoid ar | 1990 Aug | Suppression of rheumatoid factor (RF) production in rheumatoid arthritis (RA) has been variably attributed to the use of remittive agents per se or to clinical improvement associated with their use. There have been conflicting reports with regard to the influence of methotrexate (MTX) on serum RF levels in RA. We determined IgM-RF and IgA-RF levels in paired serum samples (obtained at study entry and completion) from RA patients enrolled in multicenter trials with the Cooperative Systematic Studies of Rheumatic Diseases program. After exclusion of the 14 IgM-RF-negative sera, there were samples from 30 MTX-treated patients and 52 placebo-treated patients. Changes in IgM-RF and IgA-RF levels were weakly associated with each other. Significant decreases in IgM-RF levels were observed in the MTX-treated patients, but not in the placebo group. These changes were most significant in the MTX-treated patients who improved clinically. There were significant decreases in IgA-RF levels at study completion among MTX-treated patients who had improved clinically and those who had not improved clinically, but not in the placebo group. The contributions of clinical improvement and MTX treatment to changes in serum IgM-RF and IgA-RF levels were examined using a logistic regression model. Changes in IgM-RF were strongly related to MTX treatment and, to a lesser extent, to clinical improvement; changes in IgA-RF were related only to MTX treatment. These results indicate that MTX treatment per se decreases both IgM-RF and IgA-RF levels, whereas clinical improvement correlates with decreased IgM-RF levels only.(ABSTRACT TRUNCATED AT 250 WORDS) | |
| 3416568 | Methotrexate in refractory rheumatoid arthritis. | 1988 Jun | Fourteen patients with severe rheumatoid arthritis refractory to hydroxychloroquine, gold-thioglucose, D-penicillamine and azathioprine completed a 6-month open study with oral methotrexate (2.5 to 5 mg every 12 hours, three doses weekly). Twelve of them were followed up for 12 months. Compared with pretreatment values, there was a significant reduction in duration of morning stiffness (p less than 0.01), in the number of tender or painful joints (p less than 0.02), number of swollen joints (p less than 0.01), visual analog scale, patient's assessment of joint discomfort and overall well-being (p less than 0.01) after 2, 6 and 12 months. Likewise there was an improvement in the erythrocyte sedimentation rate (p less than 0.001) C-reactive protein (p less than 0.01) and the levels of IgG, IgM and IgA (p less than 0.01). Two patients were withdrawn from the study, one for severe diarrhoea and one because of a depression. Adverse reactions during methotrexate therapy included nausea (5/16) and transaminase elevation (4/16). We conclude that this pilot study provides evidence that a weekly low dose of methotrexate is effective in the short-term treatment for patients with rheumatoid arthritis, refractory to hydroxychloroquine, auriothioglucose, D-penicillamine and azathioprine. | |
| 2670022 | New therapies for the rheumatic diseases. | 1989 | The investigational therapies of the rheumatic diseases reviewed in this issue are at various stages of clinical development. Methotrexate and sulfasalazine represent examples of chemotherapies in which the short-term efficacy and toxicities, at least in rheumatoid arthritis, have been carefully documented by controlled trials. The limited information available on cyclosporin A, combination chemotherapy, and radiotherapy is encouraging and appears to warrant additional, more extensive studies. In particular, randomized trials to determine the effects of these interventions on relevant long-term outcomes such as functional disability, organ failure, and life expectancy are necessary. Careful attention to the adverse consequences associated with these interventions, a limiting factor in many currently available therapies, will be mandatory. Disease modification by biologic agents holds the promise of ushering in an entirely new, more selective approach to therapy. A number of these biologic agents are currently at the threshold of clinical evaluation. In all likelihood, the scientific knowledge of pathogenic mechanisms operative in the rheumatic diseases gained through the use of these agents will be of equal importance to the therapeutic benefits. | |
| 2913717 | Methotrexate therapy in rheumatoid arthritis. | 1989 Feb | Rheumatoid arthritis (RA) is a common disease with a significant economic and social impact on Americans. Many patients with RA are unresponsive to or intolerant of conventional therapy or the limited therapeutic options available. For many of those patients, immunosuppressive drugs have been the mainstay of therapy. Our experience with methotrexate for these patients indicates that this drug provides symptomatic relief and improvement in objective parameters. Significant toxicity was uncommon. Methotrexate should be considered for selected patients with severe rheumatoid arthritis when conventional measures have been exhausted. | |
| 2504919 | Felty's syndrome: response to low dose oral methotrexate. | 1989 Jul | We describe a case of Felty's syndrome with persistent severe neutropenia below 200 granulocytes/mm3, splenomegaly and repeated infections. The patient did not respond to treatment with intramuscular gold salts and lithium carbonate. After 2 months of oral methotrexate administration, 7.5 mg weekly, clinical improvement was notable: she remained afebrile, neutropenia disappeared and splenomegaly regressed. This clinical and laboratory improvement persisted 5 months later. Moreover, accidental discontinuance of the drug and later readministration supported the evidence that the improvement was due to methotrexate. | |
| 1883690 | Methotrexate: mechanism of action, pharmacokinetics, clinical indications, and toxicity. | 1991 Jun | Methotrexate has become a standard therapy for the treatment of rheumatoid arthritis. This review summarizes the recent literature on low-dose methotrexate in the rheumatologic illnesses. The effect of methotrexate on in vivo rheumatoid factor production and suppression of ex vivo leukotriene B4 generation is reviewed. New information on drug interactions and pharmacokinetics is highlighted. The efficacy and toxicity of the drug in rheumatoid arthritis and other diseases are further defined. The effects of methotrexate on liver histology are also summarized. | |
| 1977296 | Rheumatoid arthritis: current concepts and management, Part 2. | 1990 Sep | Rheumatoid arthritis is a systemic disorder, but primarily involves chronic polyarticular inflammation. Conservative nondrug therapy and NSAIDs are indicated initially and are effective treatment for many RA patients. For those individuals with progressive unresponsive disease an SAARD should be used. All SAARDs exhibit severe and frequent adverse effects with the risk-to-benefit ratio being the determining factor in deciding which agent to use. The first to be used is usually a gold compound; antimalarials and penicillamine provide alternatives to gold therapy. Sulfasalazine may gain a role in the therapy of early progressive RA. Methotrexate has recently been given FDA approval for use in RA and can be used, if the first three agents fail. Azathioprine and cyclophosphamide are cytotoxic agents with an increased risk of producing malignancies, but their use is sometimes required to halt serious progressive RA. Chlorambucil or cyclosporin A are relatively toxic agents that may play a role in treating refractory RA. Corticosteroids should be used for short-term adjunctive therapy as intra-articular injections or oral therapy in individuals refractory to all other therapies. The use of SAARDs early in RA or in combination with one another is controversial. | |
| 1994912 | Synovial membrane histology and immunopathology in rheumatoid arthritis and osteoarthritis | 1991 Feb | We examined the histologic and immunopathologic features of the synovial membrane of 18 patients with rheumatoid arthritis (RA) and 12 patients with osteoarthritis (OA) who had undergone total knee arthroplasty. Patients were classified into 5 groups according to therapeutic regimen and disease: RA treated with nonsteroidal antiinflammatory drugs (NSAIDs), RA treated with NSAIDs and prednisone, RA treated with NSAIDs and methotrexate (MTX), OA treated with analgesics, and OA treated with NSAIDs. There were no significant between-group differences in the percentages or the distribution pattern of the infiltrating T cell subsets (CD4, CD8), HLA-DR, or interleukin-2 receptor-bearing cells. However, inflammatory indices, which included the thickness of the lining cell layer and the density of the mononuclear cell infiltrate, were significantly higher in the RA patients treated with prednisone and those treated with MTX (P less than 0.05). Similarly, fibrosis was markedly reduced in these 2 groups. The RA patients treated with NSAIDs alone and the 2 groups of patients with OA demonstrated similar profiles. These data suggest that prednisone and MTX may inhibit the development of fibrosis without altering the subsets of the inflammatory cell population. This observation raises the possibility that the action of these 2 drugs may be partly mediated by the suppression of inflammatory mediators that are responsible for fibroblast activation. | |
| 2167685 | Inhibition of leukotriene B4 synthesis in neutrophils from patients with rheumatoid arthri | 1990 Aug | We studied the effects of a single, oral dose of methotrexate (MTX) on arachidonic acid metabolism in neutrophils from 6 patients with rheumatoid arthritis, which were obtained 1 day before and 1 day after their usual weekly MTX dose. The 6 patients had received a mean weekly MTX dose of 9.6 mg (range 5-15) for a mean of 61.7 months (range 58-64), and none received concomitant corticosteroids. Total generation of leukotriene B4 (LTB4) in neutrophils stimulated ex vivo with 10 microM calcium ionophore A23187 for 20 minutes was significantly suppressed, by a mean of 53%, after the MTX dose compared with the predose levels (mean +/- SEM 13.0 +/- 1.4 ng/10(6) cells versus 6.0 +/- 0.9 ng/10(6) cells; P = 0.0019), reflecting a comparable suppression of both released and cell-retained LTB4. A 49% decrease in omega-oxidation products of LTB4 demonstrates that decreased LTB4 synthesis, rather than increased degradation, is responsible for the decrease in LTB4 generation. The absence of a significant change in either 3H-labeled arachidonic acid release or platelet-activating factor generation indicates that the observed decrease in LTB4 synthesis was apparently not caused by diminished phospholipase A2 activity. A 28% decrease in the total formation of the 5-lipoxygenase products 5-hydroxyeicosatetraenoic acid and the 6-trans-LTB4 diastereoisomers, and a 48% suppression of production of LTB4 plus its omega-oxidation metabolites after the MTX dose suggest inhibition of 5-lipoxygenase activity and possible suppression of leukotriene A4 epoxide hydrolase activity. | |
| 2737039 | [Methotrexate (MTX) in the treatment of rheumatoid arthritis]. | 1989 Feb | The efficacy of MTX in the treatment of 35 cases of rheumatoid arthritis (RA) was evaluated. MTX was administered orally (8 cases) or intramuscularly (27 cases) in doses of 15-20 mg per week over a 3 months period. At the completion of three months courses, all clinical parameters measured except for 15 meters walking time, including joint pain count, joint tenderness/swelling counts and scores, morning stiffness, grip strength, joint functional state and rheumatoid nodule were significantly improved (P less than 0.01 or P less than 0.05). The erythrocyte sedimentation rate and rheumatoid factor were also improved significantly after therapy. Four patients were in complete remission, 20 patients had important improvement, 10 patients had clinical improvement, and one unchanged. The drug adverse effect was mild and transient. Gastrointestinal upset was most frequently seen (45.7%), mild leukopenia occurred in 4 patients, skin rash in 2, herpes simplex in 1. No patient were withdrawn drug owing to the untoward effect. We consider that MTX is a useful and safe mode of treatment for RA. | |
| 3325643 | Methotrexate pneumonitis in rheumatoid arthritis: potential risk factors. Four case report | 1987 Dec | Methotrexate pneumonitis is emerging as one of the most unpredictable and potentially serious adverse effects associated with the use of low dose, pulse methotrexate in treating rheumatoid arthritis (RA). We report 4 new cases of methotrexate pneumonitis in patients with RA and review 6 published cases. A greater than expected proportion of patients had a smoking history, preexisting pulmonary disease and were male. Prognosis was better in those patients treated with corticosteroids. | |
| 2161306 | The in vivo effect of nonsteroidal anti-inflammatory drugs, gold sodium thiomalate and met | 1990 Jan | The generation of superoxide radicals by activated peripheral blood polymorphonuclear leukocytes from patients with rheumatoid arthritis (RA) has been measured and the in vivo effect of nonsteroidal anti-inflammatory drugs (NSAIDs) and disease remittive agents studied. Generation of superoxide radicals from RA patients was significantly decreased when compared to a control population. This was principally due to the disease rather than medications in that patients with osteoarthritis receiving NSAID generated superoxide radicals similar to that seen in the control group. RA patients receiving NSAIDs and injectable gold or methotrexate therapy showed a significant trend to normalization of superoxide radical generation when compared to those with RA receiving NSAIDs alone. We conclude that the reduced generation of superoxide radicals on activated polymorphonuclear leukocytes from patients with RA is principally a feature of the disease and that this abnormality can be partially reversed by the use of a disease remittive agent in vivo. | |
| 1920332 | The efficacy and toxicity of a constant low dose of methotrexate as a treatment for intrac | 1991 Jul | Ninety-two patients with intractable rheumatoid arthritis (RA) participated in an open prospective study of the longterm efficacy and toxicity of methotrexate (MTX), administered orally at a constant dosage of 7.5 mg/week. Twenty-four patients (25%) had to be withdrawn from the study within the first 12 months because of inefficacy or adverse reactions with a fatal outcome in 2 patients. In the remaining 68 patients, the mean duration of therapy was 19 months. Sixty-three of 92 patients (68%) experienced significant clinical improvement after one year, 23 (25%) were in clinical remission. Twenty-three of these patients initially responded well but relapsed after a median of 15 months of therapy. In 5 patients (5%) the disease activity remained status quo. Toxicity was noted at some time in 51 patients (54%), consisting of clinical side effects in 37 patients (40%) and biological abnormalities in 36 patients (39%), including 9 patients (10%) with blood and bone marrow toxicity, in whom renal function at start was normal. Two of these latter 9 patients had a fatal outcome because of an unexpected renal deterioration due to intercurrent disease. Thus, MTX at this constant low dose appears to be a temporarily valuable therapy for intractable RA. Careful monitoring is necessary in view of the potentially dangerous side effects. |